The causal effect of reproductive factors on pelvic floor dysfunction: a Mendelian randomization study.

BACKGROUND: Pelvic floor dysfunction (PFD) is an extremely widespread urogynecologic disorder, the prevalence of which increases with aging. PFD has severely affected women's quality of life and has been called a social cancer. While previous studies have identified risk factors such as vaginal delivery and obesity for PFD, other reproductive factors, including age at menarche (AAMA), have been largely overlooked. Therefore, we used a Mendelian randomization (MR) study for the first time to investigate the potential causal relationship between reproductive factors and PFD. METHODS: We obtained summary statistics from genome-wide association studies (GWAS) for female genital prolapse (FGP), stress urinary incontinence (SUI), and five reproductive factors. Two-sample Mendelian randomization analysis (TSMR) was performed to explore the causal associations between these factors. The causal effects of reproductive factors on FGP and SUI were primarily estimated using the standard inverse variance weighting (IVW) method, with additional complementary and sensitivity analyses conducted using multiple approaches. A multivariate Mendelian randomization (MVMR) study was also conducted to adjust for pleiotropic effects and possible sources of selection bias and to identify independent exposure factors. RESULTS: Our findings revealed that advanced age at first sexual intercourse (AFS) and age at first birth (AFB) exhibited negative causal effects on both FGP and SUI. AAMA showed negative causal effects solely on FGP, while age at last live birth (ALB) and age at menopause (AAMO) did not demonstrate any causal effect on either FGP or SUI. And the MVMR results showed that AFB and AFS had independent negative causal effects on FGP and SUI, respectively. CONCLUSIONS: This study, for the first time, investigates the causal relationship between reproductive factors and PFD. The results suggested a causal relationship between some reproductive factors, such as AFB and AFS, and PFD, but there were significant differences between FGPand SUI. Therefore, future studies should explore the underlying mechanisms and develop preventive measures for reproductive factors to reduce the disease burden of PFD.

Oocyte oxidative DNA damage may be involved in minimal/mild endometriosis-related infertility.

Early endometriosis is associated with infertility, and oxidative stress may play a role in the pathogenesis of disease-related infertility. This prospective case-control study aimed to compare the presence of oxidative stress markers in the follicular microenvironment and systemic circulation of infertile women with minimal/mild endometriosis (EI/II) versus individuals undergoing controlled ovarian stimulation for intracytoplasmic sperm injection (ICSI). Seventy-one blood samples (27 from infertile women with EI/II and 44 controls with tubal and/or male infertility factor) and 51 follicular fluid samples (19 EI/II and 32 controls) were obtained on the day of oocyte retrieval. Total hydroperoxides (FOX1 ), reduced glutathione, vitamin E, Superoxide dismutase, total antioxidant capacity, malondialdehyde, advanced oxidation protein products, and 8-hydroxy-2'-deoxyguanosine (8OHdG) concentrations were measured in both fluids. Women with EI/II showed higher FOX1 (8.48 ± 1.72 vs. 7.69 ± 1.71 µmol/g protein) and lower total antioxidant capacity (0.38 ± 0.18 vs. 0.46 ± 0.15 mEq Trolox/L) concentrations in serum, and higher 8OHdG concentrations (24.21 ± 8.56 vs. 17.22 ± 5.6 ng/ml) in follicular fluid compared with controls. These data implicate both systemic and follicular oxidative stress may in infertile women with EI/II undergoing controlled ovarian stimulation for ICSI. Furthermore, the elevated 8OHdG concentrations in follicular fluid of women with EI/II may be related to compromised oocyte quality.

[Female pelvic floor dysfunction from the perspectives of genetic studies].

Currently, despite the growing prevalence of female pelvic floor dysfunction, no consensus exists among researchers regarding its etiology and pathogenesis. There is no doubt, however, that this is a multifactorial disorder with a genetic predisposition. The risk for developing pelvic floor dysfunction is determined by the interaction of multiple additive genetic (mutations and/or polymorphic alleles) and environmental factors. This review of the world literature presents a rationale for searching specific molecular genetic factors shaping the structure of the genetic susceptibility to female pelvic floor dysfunction. The pelvic organ prolapse in women has been found to be associated with the rs1800012 polymorphism of the COL1A1 gene, genotype rs1800255-A/A of COL3A1 gene and the rs2228480 polymorphism of ESR1, although this data still controversial and need to be validated in the independent samples. The systematic accumulation of data, their reproduction in different populations and ethnic groups is necessary to further generalize the evidence on the pathogenesis and the functional significance of each gene variant.

Biological findings from the PheWAS catalog: focus on connective tissue-related disorders (pelvic floor dysfunction, abdominal hernia, varicose veins and hemorrhoids).

Pelvic floor dysfunction, specifically genital prolapse (GP) and stress urinary inconsistency (SUI) presumably co-occur with other connective tissue disorders such as hernia, hemorrhoids, and varicose veins. Observations on non-random coexistence of these disorders have never been summarized in a meta-analysis. The performed meta-analysis demonstrated that varicose veins and hernia are associated with GP. Disease connections on the molecular level may be partially based on shared genetic susceptibility. A unique opportunity to estimate shared genetic susceptibility to disorders is provided by a PheWAS (phenome-wide association study) designed to utilize GWAS data concurrently to many phenotypes. We searched the PheWAS Catalog, which includes the results of the PheWAS study with P value < 0.05, for genes associated with GP, SUI, abdominal hernia, varicose veins and hemorrhoids. We found pronounced signals for the associations of the SLC2A9 gene with SUI (P = 6.0e-05) and the MYH9 gene with varicose veins of lower extremity (P = 0.0001) and hemorrhoids (P = 0.0007). The comparison of the PheWAS Catalog and the NHGRI Catalog data revealed enrichment of genes associated with bone mineral density in GP and with activated partial thromboplastin time in varicose veins of lower extremity. In cross-phenotype associations, genes responsible for peripheral nerve functions seem to predominate. This study not only established novel biologically plausible associations that may warrant further studies but also exemplified an effective use of the PheWAS Catalog data.

Familial predisposition to pelvic floor dysfunction: prolapse and incontinence surgery among family members and its relationship with age or parity in a Swedish population.

OBJECTIVE: To estimate the relationship between heredity and proband's age/parity on the risk of undergoing surgery for pelvic organ prolapse and stress incontinence. STUDY DESIGN: Swedish population based study. Data from two national Swedish registers were used: the Hospital Discharge Register, National Board of Health and Welfare, containing information on all in-patient surgical procedures on Swedish hospitals, and the Multi-Generation Register, Statistics Sweden, containing information on individuals belonging to the same family. Women who had a surgical procedure for urinary incontinence or genital organ prolapse between the years 1987 and 2002 were identified (probands). Mothers and sisters of the probands were identified and information on incontinence or prolapse operations was linked to those relatives from the Hospital Discharge file, after which adjusted analyses were performed. RESULTS: Sisters to probands had a relative risk (RR) of 4.69 (95% confidence intervals (CI) 4.49-48.9) and mothers a RR of 2.17 (95% CI 2.07-2.27) for pelvic floor surgery. For sisters the risk decreased with increasing age and parity of the proband. CONCLUSION: Sisters and mothers of women operated for urinary incontinence/urogenital prolapse had a higher risk of surgery for pelvic floor conditions, in particular sisters of women operated at a young age (<50) and with a low parity. This suggests that heredity plays a lesser role for the development of pelvic floor dysfunction at older age and with increasing parity.

Phenotypic identification and classification of functional defecatory disorders using high-resolution anorectal manometry.

BACKGROUND & AIMS: Disordered defecation is attributed to pelvic floor dyssynergia. However, clinical observations indicate a spectrum of anorectal dysfunctions. The extent to which these disorders are distinct or overlap is unclear; anorectal manometry might be used in diagnosis, but healthy persons also can have abnormal rectoanal pressure gradients during simulated evacuation. We aimed to characterize phenotypic variation in constipated patients through high-resolution anorectal manometry. METHODS: We evaluated anorectal pressures, measured with high-resolution anorectal manometry, and rectal balloon expulsion time in 62 healthy women and 295 women with chronic constipation. Phenotypes were characterized by principal components analysis of high-resolution anorectal manometry. RESULTS: Two healthy persons and 71 patients had prolonged (>180 s) rectal balloon expulsion time. A principal components logistic model discriminated healthy people from patients with prolonged balloon expulsion time with 75% sensitivity and a specificity of 75%. Four phenotypes discriminated healthy people from patients with abnormal balloon expulsion times; 2 phenotypes discriminated healthy people from those with constipation but normal balloon expulsion time. Phenotypes were characterized based on high anal pressure at rest and during evacuation (high anal), low rectal pressure alone (low rectal) or low rectal pressure with impaired anal relaxation during evacuation (hybrid), and a short anal high-pressure zone. Symptoms were not useful for predicting which patients had prolonged balloon expulsion times. CONCLUSIONS: Principal components analysis of rectoanal pressures identified 3 phenotypes (high anal, low rectal, and hybrid) that can discriminate among patients with normal and abnormal balloon expulsion time. These phenotypes might be useful to classify patients and increase our understanding of the pathogenesis of defecatory disorders.

Epithelial Bmp (Bone morphogenetic protein) signaling for bulbourethral gland development: a mouse model for congenital cystic dilation.

The bulbourethral gland (BUG) is a male-specific organ, which secretes part of the semen fluid. As the BUG is located in the deep pelvic floor, its developmental process is still unclear. Bone morphogenetic protein (Bmp) signaling plays pivotal roles in various organs. However, the function of Bmp signaling for BUG development is still unclear. The present study aimed to elucidate the role of Bmp signaling in the development of the BUG. We observed the prominent nuclear accumulation of phosphorylated (p) SMAD1/5/8, the downstream molecules of Bmp signaling, during BUG epithelial development. These results suggest that Bmp signaling contributes to BUG development. Bmp receptor1a (Bmpr1a) is known as the major type 1 signal transducer in some organogeneses. To analyze the Bmp signaling function for BUG development, we examined epithelial cell-specific Bmpr1a gene conditional mutant mice utilizing the tamoxifen-inducible Cre recombinase system. We observed cystic dilation and epithelial hyperplasia of the BUG in the Bmpr1a conditional knockout mice. The mutant cystic BUG specimens also showed inflammatory lesions. These BUG abnormalities resembled some of the BUG malformations observed in human congenital syndromes. The current study suggests that Bmp signaling possesses an essential role in BUG development and homeostasis. This would be the first report showing that the mutation of the Bmpr1a gene in the BUG epithelia phenocopied some abnormalities of human congenital syndromes affecting the BUG duct.